Variant classification summary

NM_000051.4:c.8419-7T>G

ATM · NP_000042.3:p.? · NM_000051.4

GRCh37: chr11:108216463 T>G · GRCh38: chr11:108345736 T>G

Gene: ATM Transcript: NM_000051.4

Final call

VUS

PM2 supporting PP3 supporting

Variant details

Gene

ATM

Transcript

NM_000051.4

Protein

NP_000042.3:p.?

gnomAD AF

ClinVar

Uncertain significance

OncoKB

Classification rationale

Interpretation summary

Generated evidence synthesis

1

NM_000051.4:c.8419-7T>G is located 7 bases upstream of the exon 58 acceptor site in ATM and is absent from gnomAD v2.1, v4.1, and gnomAD-Canada v1.0 (PM2_Supporting).

2

SpliceAI predicts a strong splicing impact with a maximum delta score of 0.90 (DS_AL=0.90, DS_AG=0.86), meeting the ATM VCEP PP3_Supporting threshold for intronic variants outside canonical splice sites (PP3_Supporting).

3

The variant is outside the canonical +/-1,2 splice acceptor consensus, and no RNA-based evidence of aberrant splicing is available; PVS1 is therefore not met under the ATM VCEP PVS1 decision tree.

4

No functional studies, segregation data, case-control data, or variant-specific literature are available. ClinVar classifies this variant as Uncertain significance (1 submitter, ClinVarID 3325300).

Final determination: No criteria-combination rule matched the adjudicated criteria in the Richards et.al., 2015 - Combining rules v1.5.0 framework, so the variant remains a Variant of Uncertain Significance pending human review.

Criteria assessment

ACMG/AMP criteria review

Criteria shown when status is available

All criteria require review: For research and educational purposes only.

Criterion	Status	Rationale	Evidence used
PVS1	Not met	Variant is located at c.8419-7 (7 bases upstream of exon 58 acceptor site), which is outside the canonical +/-1,2 splice acceptor consensus. The ATM VCEP PVS1 framework permits PVS1(RNA) only when RNA-based evidence of aberrant splicing is available; no such data exist for this variant. SpliceAI prediction alone does not satisfy PVS1 requirements under the ATM VCEP decision tree.	spliceai vcep_atm_pvs1_1_5 pvs1_variant_assessment
PS1	Not met	Per the ATM VCEP PS1 Splicing table, for variants located outside the donor/acceptor +/-1,2 dinucleotide positions the baseline predictive code is PP3. PS1 requires a known pathogenic/likely pathogenic reference variant at the same nucleotide or within the same donor/acceptor motif with a matching or weaker splice prediction. No such comparator variant has been identified for c.8419-7T>G.	vcep_atm_ps1_1_5
PS2	N/A	VCEP HBOP v1.5.0 specifies de novo criteria (PS2/PM6) are not used for ATM; informative de novo occurrences have not been observed and de novo autosomal recessive conditions are unlikely to be informed by phase.	cspec
PS3	Not met	No variant-specific functional studies are available. The ATM VCEP PS3/BS3 calibration tables (clingen_hbop_atm_supplementary_tables_1_and_2_v1.xlsx) list approved kinase activity and radiosensitivity assays but this variant has not been tested in any of them. The Suppl_TableS1 (PMID 40580951) systematic functional screen does not include c.8419-7T>G.	vcep_clingen_hbop_atm_supplementary_tables_1_and_2_v1 vcep_suppl_tables1_pmid_40580951
PS4	Not met	No case-control studies or proband enrichment data are available for this variant. The sole literature source (PMID 25394175) is a practice guideline that does not mention NM_000051.4:c.8419-7T>G.	PMID:25394175
PS5	Not met	This criterion is not part of the ATM VCEP HBOP v1.5.0 specification. Under generic ACMG/AMP, PS5 requires a reputable source to have reported the variant as pathogenic with evidence not independently available. ClinVar classifies this variant as Uncertain significance (1 star, criteria provided single submitter), not pathogenic.	clinvar
PM1	N/A	VCEP HBOP v1.5.0 specifies PM1 is not applicable for ATM; benign and pathogenic variants are known to occur within the same domains and germline mutational hotspots are not well defined at this time.	cspec
PM2	Met	NM_000051.4:c.8419-7T>G is absent from gnomAD v2.1, v4.1, and gnomAD-Canada v1.0 (allele frequency = 0.0%), meeting the ATM VCEP PM2_Supporting threshold of ≤0.001% in gnomAD v4.	gnomad_v2 gnomad_v4 gnomad_canada cspec
PM5	N/A	The ATM VCEP PM5 rule applies only to frameshifting/truncating variants with premature termination codons upstream of p.Arg3047, or splice variants where PVS1_VS(RNA) has been applied with high-quality observed splicing impact and NMD-prone outcome. This is an intronic substitution at c.8419-7 without PVS1(RNA) applied.	cspec pm5_candidates
PM6	N/A	VCEP HBOP v1.5.0 specifies de novo criteria (PS2/PM6) are not used for ATM; informative de novo occurrences have not been observed and de novo autosomal recessive conditions are unlikely to be informed by phase.	cspec
PP1	Not met	No segregation data are available for this variant. The ATM VCEP PP1 rule requires segregation analysis in families with ataxia-telangiectasia (AR condition); no such studies have been reported.
PP2	N/A	VCEP HBOP v1.5.0 specifies PP2 is not applicable for ATM; ATM does not have a defined low rate of missense benign variation.	cspec
PP3	Met	SpliceAI predicts a strong splice impact with a maximum delta score of 0.90 (DS_AL=0.90, DS_AG=0.86), exceeding the ATM VCEP PP3_Supporting threshold of ≥0.2 for intronic variants outside donor/acceptor +/-1,2 sites. PP3 for splice predictions is applied independently here as PVS1 is not met. The variant is located 7 bases upstream of the exon 58 acceptor site, where SpliceAI predicts acceptor loss.	spliceai cspec
PP4	N/A	VCEP HBOP v1.5.0 specifies PP4 is not applicable; for autosomal dominant breast cancer, multiple genetic etiologies preclude phenotype specificity; for autosomal recessive A-T, this evidence is built into the PM3/BP2 table.	cspec
PP5	N/A	VCEP HBOP v1.5.0 designates PP5 as not applicable for this VCEP.	cspec
BA1	Not met	The variant is absent from gnomAD v4.1 (grpmax filtering AF = 0.0%), which does not meet the ATM VCEP BA1 Stand Alone threshold of >0.5%.	gnomad_v4 cspec
BS1	Not met	The variant is absent from gnomAD v4.1 (grpmax filtering AF = 0.0%), which does not meet the ATM VCEP BS1 Strong threshold of >0.05%.	gnomad_v4 cspec
BS2	N/A	VCEP HBOP v1.5.0 designates BS2 as not applicable for this VCEP.	cspec
BS3	Not met	No functional studies demonstrating rescue of ATM-specific features or radiosensitivity are available. The ATM VCEP BS3 calibration tables list approved assays but this variant has not been tested. The Suppl_TableS1 (PMID 40580951) high-throughput functional screen does not include c.8419-7T>G.	vcep_clingen_hbop_atm_supplementary_tables_1_and_2_v1 vcep_suppl_tables1_pmid_40580951
BS4	N/A	VCEP HBOP v1.5.0 designates BS4 as not applicable for this VCEP.	cspec
BP1	N/A	VCEP HBOP v1.5.0 designates BP1 as not applicable for this VCEP.	cspec
BP2	Not met	No proband data are available to score against the ATM PM3/BP2 table. The variant has not been reported in any A-T-affected individuals or unaffected individuals with a second ATM pathogenic variant. Without proband observations, no BP2 points can be assigned.	vcep_atm_pm3_bp2_1_5
BP4	Not met	SpliceAI predicts strong splice impact (max delta = 0.90), far exceeding the ATM VCEP BP4 Supporting threshold of ≤0.1 for benign splicing prediction. This criterion cannot be applied.	spliceai cspec
BP5	N/A	VCEP HBOP v1.5.0 specifies BP5 is not applicable for ATM; cases with multiple pathogenic variants have been observed with no noticeable difference in phenotype, and ATM has low penetrance with higher tolerance in the general population.	cspec
BP6	N/A	VCEP HBOP v1.5.0 specifies BP6 is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.	cspec
BP7	N/A	The ATM VCEP BP7 prediction-based rule applies only to deep intronic variants further than -21 from the acceptor site; this variant is at -7, which does not qualify. BP7(RNA) requires RNA evidence demonstrating absence of aberrant splicing, which is not available.	cspec
BP3	N/A	VCEP HBOP v1.5.0 specifies BP3 is not applicable for ATM; in-frame deletions/insertions in repetitive regions are not relevant to this intronic substitution.	cspec
PM3	N/A	This is an intronic substitution assessed in a case without proband data for ATM recessive disease (ataxia-telangiectasia); PM3 is trivially not applicable in this context.
PM4	N/A	VCEP HBOP v1.5.0 specifies PM4 is used only for stop-loss variants. NM_000051.4:c.8419-7T>G is an intronic substitution, not a stop-loss variant.	cspec

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